This piece by Paul Nelson predictably distorts the actual take home message of this paper.

Basically, the (original) Levinthal paradox related to protein folding was not a paradox, it was a calculation that showed the immense dimensions of folding space. Levinthal simply concluded the conformational space is so vast that a protein cannot fold by random conformational search. That is, there is no time to visit a significant part of the folding space to search out the best energetic solution – what we call the global minimum. Rather – he suggested – there must be mechanisms encoded in the protein sequence, i.e. the protein follows some path(s) from an unfolded to a folded state. The necessity of this conclusion can be stressed by calling the apparent contradiction between the number of conformations and the time it actually takes for a protein to fold, a “paradox”.

This paper makes two points. For one, nobody took notice of the analogy of protein folding and the assembly of the interactome. Their calculations only show that the numbers are even bigger here. It does not really matter how big they are – even 10^7200 is unimaginable, thus it serves the purpose.

The conclusion that there are pathyways of assembly, is trivial, everybody thinks it this way. Their “paradox” only puts emphasis on the magnitude of the problem.

The second, more circumstantial and more serious conclusion they draw is that the analogy is only virtual: whereas protein folding leads to the global energy minimum, the interactome is not in an energy minimum, it is in a “steady state”, and requires continuous energy to maintain. They purport it cannot form from its components, i.e. the interactome cannot “fold” if taken apart. It could only form once during evolution, and its assembled state contains the very information needed for its assembly. It is a rather philosophical conclusion, and has many consequences, far less trivial than folding mechanisms and assembly pathways.